Modulators of alpha-synuclein proteolysis and associated methods of use

Patent metadata

Field	Value
Publication number	US-12594264-B2
Application number	US-202318309867-A
Country	US
Kind code	B2
Filing date	Sep 18, 2023
Priority date	Aug 20, 2018
Publication date	Apr 7, 2026
Grant date	Apr 7, 2026

Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of α-synuclein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon. Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

First claim

What is claimed is:

1 . A bifunctional compound having the chemical structure:
ULM-L-PTM, or a pharmaceutically acceptable salt thereof, wherein: (a) ULM is;

wherein:
X 1 , X 2 are each independently selected from a bond, O, NR Y3 , CR Y3 R Y4 , C═O, C═S, SO, and SO 2 ;
R Y3 , R Y4 are each independently selected from H, linear or branched C 1 -C 6 alkyl optionally substituted by 1 or more halo, and C 1 -C 6 alkoxyl optionally substituted by 0-3 R P groups;
R P is independently selected from H, halo, —OH, C 1 -C 3 alkyl, and C═O;
W 3 is selected from an optionally substituted T, an optionally substituted -T-N(R 1a R 1b )X 3 , an optionally substituted -T-N(R 1a R 1b ), an optionally substituted -T-aryl, an optionally substituted -T-heteroaryl, an optionally substituted T-biheteroaryl, an optionally substituted -T-heterocycle, an optionally substituted -T-biheterocycle, an optionally substituted —NR 1 -T-aryl, an optionally substituted —NR 1 -T-heteroaryl and an optionally substituted —NR 1 -T-Heterocycle;
X 3 is selected from C═O, R 1 , R 1a , and R 1b ;
each of R 1 , R 1a , R 1b is independently selected from H, linear or branched C 1 -C 6 alkyl group optionally substituted by 1 or more halo or —OH groups, R Y3 C═O, R Y3 C═S, R Y3 SO, R Y3 SO 2 , N(R Y3 R Y4 ) C═O, N(R Y3 R Y4 ) C═S, N(R Y3 R Y4 ) SO, and N(R Y3 R Y4 ) SO 2 ;
T is selected from an optionally substituted alkyl, —(CH 2 ) n — group, wherein each one of the methylene groups is optionally substituted with one or two substituents selected from halogen, methyl, optionally substituted alkoxy, and a linear or branched C 1 -C 6 alkyl group optionally substituted by 1 or more halogen, C(O) NR 1 R 1a , or NR 1 R 1a or R 1 and R 1a are joined to form an optionally substituted heterocyclyl, or —OH groups or an amino acid side chain optionally substituted; and
n is 0, 1, 2, 3, 4, 5, or 6,
W 4 is

 R 14a and R 14b , are each independently selected from H, haloalkyl, and optionally substituted alkyl;
W 5 is an optionally substituted phenyl or an optionally substituted 5-10-membered heteroaryl,
R 15 is selected from H, halogen, CN, OH, NO 2 , N R 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a COR 14b , SO 2 NR 14a R 14b , NR 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted cyclo-heteroalkyl; and
is the attachment of a chemical linker moiety (L);

(b) PTM is selected from:

wherein:
A, B, C, D, and E are independently selected from an optionally substituted 5- or 6-membered aryl or an optionally substituted 5- or 6-membered heteroaryl, and the optional substitutions are 1, 2, 3, or 4 substituents independently selected from H, C 1 -C 6 alkyl, O, N, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, carbonyl, amino, alkylamino, dialkylamino, cyano, nitro, and —SO 2 — or an optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, and the optional substitutions are 1, 2, 3, or 4 substituents independently selected from H, alkyl, O, N, halogen, C 1 -C 6 haloalkyl, alkoxy, hydroxy, carbonyl, amino, alkylamino, dialkylamino, cyano, nitro, and —SO 2 —, wherein contact between circles indicates ring fusion;
M 1 , M 2 , and M 3 are independently selected from a single bond; O—; —S—; —NR 100 —; —SO 2 —; —S(O)—; —SO 2 NH—; —C(O)—; —C(O) NH—; and an optionally substituted C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, wherein a carbon of the alkyl group may be replaced with a group independently selected from —O—, —S—, —NR 100 —, —SO 2 —, —S(O)—, —SO 2 NH—, —C(O)— or —C(O)NH—, and the optional substitutions are selected from halogen, amino, alkyl or a haloalkyl, and a two to four carbon conjugated alkenyl fragment; an alkynyl fragment; and a two to four carbon conjugated alkenyl or alkynyl fragment, wherein at least one of the carbon of the alkenyl or alkynyl group may be part of A, B, C, or D;
each R 100 is independently selected from H, C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 haloalkyl;
indicates the attachment of a chemical linker moiety (L); and

(c) L is a chemical linker moiety comprising an optionally substituted C 1 -C 50 alkyl, wherein:
each carbon is optionally substituted with CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 0-6 R L1 and/or R L2 groups, C 5-13 spirocycloalkyl optionally substituted with 0-9 R L1 and/or R L2 groups, C 3-11 heteocyclyl optionally substituted with 0-6 R L1 and/or R L2 groups, C 5-13 spiroheterocyclyl optionally substituted with 0-8 R L1 and/or R L2 groups, aryl optionally substituted with 0-6 R L1 and/or R L2 groups, and heteroaryl optionally substituted with 0-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R L5 groups; and
R L1 , R L2 , R L3 , R L4 and R L5 are, each independently selected from H, halo, C 1 -C 8 alkyl, O C 1 -C 8 alkyl, S C 1 -C 8 alkyl, NH C 1 -C 8 alkyl, N(C 1 -C 8 alkyl) 2 , C 3 -C 11 cycloalkyl, aryl, heteroaryl, C 3 -C 11 heterocyclyl, OC 3 -C 8 cycloalkyl, SC 3 -C 8 cycloalkyl, NHC 3 -C 8 cycloalkyl, N(C 3 -C 8 cycloalkyl) 2 , N(C 3 -C 8 cycloalkyl) (C 1 -C 8 alkyl), OH, NH 2 , SH, SO 2 C 1 -C 8 alkyl, P(O)(OC 1 -C 8 alkyl) (C 1 -C 8 alkyl), P(O)(OC 1 -C 8 alkyl) 2 , CC≡C 1 -C 8 alkyl, CCH, CH═CH(C 1 -C 8 alkyl), C(C 1 -C 8 alkyl)=CH(C 1 -C 8 alkyl), C(C 1 -C 8 alkyl)=C(C 1 -C 8 alkyl) 2 , Si(OH) 3 , Si(C 1 -C 8 alkyl) 3 , Si(OH)(C 1 -C 8 alkyl) 2 , COC 1 -C 8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1 -C 8 alkyl, SO 2 N(C 1 -C 8 alkyl) 2 , SONHC 1 -C 8 alkyl, SON(C 1 -C 8 alkyl) 2 , CONHC 1 -C 8 alkyl, CON(C 1 -C 8 alkyl) 2 , N(C 1 -C 8 alkyl)CONH(C 1 -C 8 alkyl), N(C 1 -C 8 alkyl)CON(C 1 -C 8 alkyl) 2 , NHCONH(C 1 -C 8 alkyl), NHCON(C 1 -C 8 alkyl) 2 , NHCONH 2 , N(C 1 -C 8 alkyl)SO 2 NH(C 1 -C 8 alkyl), N(C 1 -C 8 alkyl) SO 2 N(C 1 -C 8 alkyl) 2 , NHSO 2 NH(C 1 -C 8 alkyl), NHSO 2 N(C 1 -C 8 alkyl) 2 , and NHSO 2 NH 2 .

2 . The compound according to claim 1 , wherein the ULM is:

wherein:
W 3 is selected from an optionally substituted aryl, optionally substituted heteroaryl, and

R 9 and R 10 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, and haloalkyl; or R 9 , R

Assignees

• Arvinas Operations Inc

Inventors

• Crew Andrew P
• Dong Hanqing
• Berlin Michael
• Sparks Steven M

Classifications

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/4245

  Oxadiazoles · CPC title